Cancer is the number two killer disease in the US, second to heart disease. In particular, cancers of the human reproductive organs, such as ovarian, prostate and breast, kill millions of people annually worldwide. Although there are several therapeutics against these cancers, aggressive forms remain problematic to treat. For example, although there are myriad hormone-based therapeutics against breast cancer, hormone insensitive breast cancer such as triple negative breast cancer remains difficult to treat.
G-quadruplexes have shown great promise as chemotherapeutic targets, likely by inhibiting telomere elongation or downregulating oncogene expression. There have been many G-quadruplex ligands developed over the years but only a few have drug-like properties. Consequently only a few G-quadruplex ligands have entered clinical trials as cancer chemotherapeutic agents. In this regard, there are ˜376,000 guanine-rich regions in the human genome, which have the potential to form G-quadruplexes, including those at the telomere end and promoter regions of some cancer-related genes. Guanine tracts in RNA are known to form G-quadruplexes in vivo but the formation of G-quadruplexes in chromosomal DNA has been a matter of debate due to the fact that the guanine tracts in chromosomal DNA can also form duplexes with complementary tracts of cytosines. After many years of fierce debate regarding a biological role for DNA G-quadruplexes in vivo, acceptance is now growing that DNA G-quadruplexes might indeed form in vivo and that there could be biological consequences of G-quadruplex formation in chromosomal DNA. Firstly, it has been demonstrated that fluorogenic G-quadruplex-specific ligands could become fluorescent inside cells, especially during cell division, when single stranded regions of chromosomal DNA are created during DNA replication. Secondly, G-quadruplex-specific antibodies have been used to provide compelling evidence that G-quadruplexes form in vivo. Additionally, biophysical approaches have demonstrated that synthetic G-rich oligonucleotides could form G-quadruplex structures in vivo.
If G-quadruplex formation in vivo has a biological consequence, then small molecules that target and stabilize these structures could have therapeutic value. In animal chromosomes, the telomerase enzyme (which is up-regulated in certain cancers) is responsible for maintaining the telomere length thereby rendering cancer cells immortal. The telomere is G-rich and has been shown via many biophysical experiments to be capable of forming G-quadruplexes. Many compounds that bind to G-quadruplexes have been shown to inhibit the activity of telomerase and some have even shown interesting anti-proliferative properties when added to cancer cells. In addition to telomeres, G-quadruplexes are present in the promoter regions a number of cancer-related genes such as c-myc, BCL-2, KRAS, c-kit and VEGF, where they are involved in the regulation of transcription of these genes by disrupting binding of transcription factors.
In light of these potential important biological roles of G-quadruplexes, there is a need for developing G-quadruplex-selective ligands for both fundamental studies (for example, fluorescent ligands that will allow for studying G-quadruplexes in vivo) and also drug-like molecules that will have suitable binding properties that will allow for selective targeting of G-quadruplexes related to cancer and other diseases. The present disclosure meets these and other needs.
Notwithstanding the need for improved agents for binding G-quadruplexes, other targets involved in a variety of conditions also need improved targeting agents. For example, the poly-(ADP)-ribose polymerases (PARP) enzymes belong to a family of proteins that are mainly involved in DNA repair and programmed cell death. Initiation of DNA damage is vital in many cancer therapies, especially chemo- and radiotherapy, and other biological processes. Because PARP enzymes have an important role in the repair of DNA damage, they are considered to be a promising target for drug development, and multiple PARP inhibitors are under development and various stages of preclinical testing. However, there remains an ongoing need for improved PARP inhibitors. Likewise, a wide variety of kinases are involved in the development, progression and recurrence of a variety of cancers, and many other disorders, such as diabetes, Alzheimer's disease, neurological pain, inflammation, pulmonary fibrosis, rheumatoid arthritis, diseases which require anticoagulants, polycystic kidney disease, and conditions that wold benefit from improved immune modulators. There remains an ongoing need for improved kinase inhibitors. Moreover, there are few if any compounds that have multi-pronged yet specific against disparate targets, such as kinases, PARP enzymes, and G-quadraplexes. Thus, compounds that can affect all three of these very distinct cancer related targets would be highly desirable. The present disclosure meets this need.